Research ArticleCancer

B cell acute lymphoblastic leukemia cells mediate RANK-RANKL–dependent bone destruction

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Science Translational Medicine  16 Sep 2020:
Vol. 12, Issue 561, eaba5942
DOI: 10.1126/scitranslmed.aba5942

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Out-RANKing bone damage in leukemia

B cell acute lymphoblastic leukemia is the most common type of cancer in children. Although this malignancy is often curable, it can cause multiple complications affecting the bone, sometimes even before the leukemia itself is diagnosed. To figure out what mediates the bone damage, Rajakumar et al. analyzed leukemia samples derived from human patients and performed mechanistic experiments in mouse models of both genetically engineered and transplanted cancer. They identified receptor activator of nuclear factor κB (RANK) signaling as a key culprit and showed that targeting this pathway in a patient-derived xenograft mouse model protected the bone from leukemia-induced destruction.


Although most children survive B cell acute lymphoblastic leukemia (B-ALL), they frequently experience long-term, treatment-related health problems, including osteopenia and osteonecrosis. Because some children present with fractures at ALL diagnosis, we considered the possibility that leukemic B cells contribute directly to bone pathology. To identify potential mechanisms of B-ALL–driven bone destruction, we examined the p53−/−; Rag2−/−; Prkdcscid/scid triple mutant (TM) mice and p53−/−; Prkdcscid/scid double mutant (DM) mouse models of spontaneous B-ALL. In contrast to DM animals, leukemic TM mice displayed brittle bones, and the TM leukemic cells overexpressed Rankl, encoding receptor activator of nuclear factor κB ligand. RANKL is a key regulator of osteoclast differentiation and bone loss. Transfer of TM leukemic cells into immunodeficient recipient mice caused trabecular bone loss. To determine whether human B-ALL can exert similar effects, we evaluated primary human B-ALL blasts isolated at diagnosis for RANKL expression and their impact on bone pathology after their transplantation into NOD.Prkdcscid/scidIl2rgtm1Wjl/SzJ (NSG) recipient mice. Primary B-ALL cells conferred bone destruction evident in increased multinucleated osteoclasts, trabecular bone loss, destruction of the metaphyseal growth plate, and reduction in adipocyte mass in these patient-derived xenografts (PDXs). Treating PDX mice with the RANKL antagonist recombinant osteoprotegerin–Fc (rOPG-Fc) protected the bone from B-ALL–induced destruction even under conditions of heavy tumor burden. Our data demonstrate a critical role of the RANK-RANKL axis in causing B-ALL–mediated bone pathology and provide preclinical support for RANKL-targeted therapy trials to reduce acute and long-term bone destruction in these patients.

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